Enabling Task-Specific Volitional Motor Functions via Spinal Cord Neuromodulation in a Human With Paraplegia

Grahn, Peter J.; Lavrov, Igor; Sayenko, Dimitry G.; Straaten, Meegan G. Van; Gill, Megan L.; Strommen, Jeffrey A.; Calvert, Jonathan S.; Drubach, Dina I.; Beck, Lisa A.; Linde, Margaux B.; Thoreson, Andrew R.; Lopez, Cesar; Mendez, Aldo A; Gad, Parag; Gerasimenko, Yury; Edgerton, V. Reggie; Zhao, Kristin D.; Lee, Kendall H.

doi:10.1016/j.mayocp.2017.02.014

Cited by 175 publications

(194 citation statements)

References 36 publications

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“…5B). Cervical anastomoses were more common on the left side (44) compared to the right side (33), same as for lumbar segments, with more anastomoses on the left side (6) compared to the right (2). The most consistent inter-root anastomoses were found on the left side in segments C3-C4, which was confirmed in all 9 cadavers (Fig.…”

Section: Fig 4 Is About Heresupporting

confidence: 64%

Segment-specific orientation of the dorsal and ventral roots for precise therapeutic targeting of human spinal cord

Mendez

Islam

Latypov

et al. 2020

Preprint

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One Sentence Summary: This is the first detailed analysis of the segment-specific dorsal and ventral spinal roots spatial orientation measured and correlated to the anatomical landmarks of the spinal cord and vertebral column for human.Abstract: An understanding of spinal cord functional neuroanatomy is essential for diagnosis and treatment of multiple disorders including, chronic pain, movement disorders, and spinal cord injury. Till now, no information is available on segment-specific spinal roots orientation in humans. In this study we collected neuroanatomical measurements of the dorsal and ventral roots from C2-L5, as well as spinal cord and vertebral bone measurements from adult cadavers. Spatial orientation of dorsal and ventral roots were measured and correlated to the anatomical landmarks of the spinal cord and vertebral column. The results show less variability in rostral root angles compared to the caudal angles across all segments. Dorsal and ventral rootlets were oriented mostly perpendicular to the spinal cord at the cervical level and demonstrate more parallel orientation at the thoracic and lumbar segments. The number of rootlets was the highest in dorsal cervical and lumbar segments. Spinal cord transverse diameter and size of the dorsal columns were largest at cervical and lumbar segments. The strongest correlation was found between the length of intervertebral foramen to rostral rootlet and vertebral bone length. These results could be used to locate spinal roots and spinal cord landmarks based on bone marks on CT or X-rays. These results also provide background for future correlations between anatomy of spinal cord and spinal column structures that could improve stereotactic surgical procedures and electrode positioning for spinal cord neuromodulation.Intervertebral foramen to rostral rootlet distance: Similar to previous measurement, intervertebral foramen to rostral rootlet distance was gradually increased to the greatest values at lumbar segments (9.59 ± 2.55 cm) (p<0.001) (Fig. 1G). This distance at C2 segment was 1.55 ± 0.42 cm and it did not change significantly throughout cervical segments till C7, where C7 (2.01 ± 0.08 cm) and C8 (2.27 ± 0.22 cm) were significantly greater compare to C5. Lower cervical and upper thoracic segments did not vary significantly till T3, where there it increased (4.05 ± 0.63 cm). No other major variations were observed across the rest of thoracic segments except for T12 (5.68 ± 0.92 cm) that was significantly longer compare to T1-T10. T12, L1, and L2 segments did not vary, but L3 (10.27 ± 2.23 cm) showed significant increase compared to L1. No major variations were observed for the rest of lumbar segments, although at L5 (12.66 ± 1.50 cm) it was significantly longer than at L2 (Fig. 1I, purple line).

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Section: Fig 4 Is About Heresupporting

confidence: 64%

Segment-specific orientation of the dorsal and ventral roots for precise therapeutic targeting of human spinal cord

Mendez

Islam

Latypov

et al. 2020

Preprint

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“…Previous studies have shown that EES enabled a greater number of steps compared to just Quipazine administration 33 . Additionally, previous reports found that Quipazine-induced stepping was dose-dependent with respect to achieving higher toe height during swing phase compared to Quipazine and EES combined stepping 33 , suggesting the synergistic effect could be due to an increased state of excitability within spinal sensorimotor networks achieved by Quipazine, which can be modulated by afferent feedback and EES to induce robust motor outputs and improved stepping performance 33 In recent clinical studies [11][12][13] , a wide range of stimulation parameters were used to produce activity-dependent modulation of spinal sensorimotor networks, indicating a clear lack of information available to investigators during stimulation parameter optimization. Additionally, it remains unknown how various EES parameters influence human spinal circuit activity and longterm plasticity over the course of motor training.…”

Section: Discussionmentioning

confidence: 95%

“…Additionally, over the last few years, investigations using EES have shown it hold great potential to improve function in humans with spasticity 9,10 and restoration of motor control after spinal cord injury [11][12][13][14] .…”

Section: Introductionmentioning

confidence: 99%

“…Targeting dorsal spinal cord structures and activation spinal CPG, epidural electrical stimulation (EES) has shown promise to restore functions after paralysis due to SCI [11][12][13][14] . Using rodent models of either partial or complete SCI, significant progress has been made in understanding underlying mechanisms by which EES alters spinal sensorimotor activity to enable functions [23][24][25][26][27][28][29][30] .…”

Section: Introductionmentioning

confidence: 99%

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Multifactorial motor behavior assessment for real-time evaluation of emerging therapeutics to treat neurologic impairments

Islam

Cuellar

Felmlee

et al. 2019

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Conflict of interestThe authors declare no conflicts of interest. AcknowledgementsThe authors thanks Mr. Seungleal (Brian) Paek for surgical and experimental assistance related to the Parkinsonian model. Finally, the authors thank Mayo Clinic's Division of Engineering for their support to design and construct the multifactorial assessment system. AbstractIntegrating multiple assessment parameters of motor behavior is critical for understanding neural activity dynamics during motor control in both intact and dysfunctional nervous systems.Here, we described a novel approach (termed Multifactorial Behavioral Assessment (MfBA)) to integrate, in real-time, electrophysiological and biomechanical properties of rodent spinal sensorimotor network activity with behavioral aspects of motor task performance. Specifically, the MfBA simultaneously records limb kinematics, multi-directional forces and electrophysiological metrics, such as high-fidelity chronic intramuscular electromyography synchronized in time to spinal stimulation in order to characterize spinal cord functional motor evoked potentials (fMEPs). Additionally, we designed the MfBA to incorporate a body weight support system to allow bipedal and quadrupedal stepping on a treadmill and in an open field environment to assess function in rodent models of neurologic disorders that impact motor activity This novel approach was validated using, a neurologically intact cohort, a cohort with unilateral Parkinsonian motor deficits due to midbrain lesioning, and a cohort with complete hind limb paralysis due to T8 spinal cord transection. In the SCI cohort, lumbosacral epidural electrical stimulation (EES) was applied, with and without administration of the serotonergic agonist Quipazine, to enable hind limb motor functions following paralysis. The results presented herein demonstrate the MfBA is capable of integrating multiple metrics of motor activity in order to characterize relationships between EES inputs that modulate mono-and polysynaptic outputs from spinal circuitry which in turn, can be used to elucidate underlying electrophysiologic mechanisms of motor behavior by synchronizing these datasets to metrics of movement and behavior. These results also demonstrate that proposed MfBA is an effective tool to integrate biomechanical and electrophysiology metrics, synchronized to therapeutic inputs such as EES or pharmacology, during body weight supported treadmill or open field motor activities, to target a high range of variations in motor behavior as a result of neurological deficit at the different levels of CNS.

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“…Interestingly, participants on those trials have also experienced improvements in autonomic function, namely cardiovascular, sexual, and voiding, among others. Additionally, reports on other neurological conditions have shown benefits from EES [1][2][3][4][5][6][7][8][9][10]. Regardless the wide application of this technique, there is still limited understanding of the mechanisms of EES effect on spinal circuitry.…”

Section: Introductionmentioning

confidence: 99%

Changes in spinal cord hemodynamic reflect modulation of spinal network with different parameters of epidural stimulation

Tang

Cuellar

Song

et al. 2019

Preprint

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In this study functional ultrasound (fUS) imaging has been implemented to explore the local hemodynamic response induced by electrical epidural stimulation and to study real-time in vivo functional changes of the spinal cord, taking advantage of the superior spatiotemporal resolution provided by fUS.By quantifying the hemodynamic and electromyographic response features, we tested the hypothesis that the transient hemodynamic response of the spinal cord to electrical epidural stimulation could reflect modulation of the spinal circuitry and accordingly respond to the changes in parameters of electrical stimulation. The results of this study for the first time demonstrate that the hemodynamic response to electrical stimulation could reflect functional organization of the spinal cord. Response in the dorsal areas to epidural stimulation was significantly higher and faster compared to the response in ventral spinal cord. Positive relation between the hemodynamic and the EMG responses was observed at the lower frequencies of epidural stimulation (20 and 40 Hz), which according to our previous findings can facilitate spinal circuitry after spinal cord injury, compared to higher frequencies (200 and 500 Hz). These findings suggest that different mechanisms could be involved in spinal cord hemodynamic changes during different parameters of electrical stimulation and for the first time provide the evidence that functional organization of the spinal cord circuitry could be related to specific organization of spinal cord vasculature and hemodynamic. Significance Statement Electrical epidural stimulation (EES) has been successfully applied to control chronic refractory pain and was evolved to alleviate motor impairment after spinal cord injury, in Parkinson's disease, and other neurological conditions. The mechanisms underlying the EES remain unclear, and current methods for monitoring EES are limited in sensitivity and spatiotemporal resolutions to evaluate functional changes in response to EES. We tested the hypothesis that the transient hemodynamic response of the spinal cord to EES could reflect modulation of the spinal cord circuitry and accordingly respond to the changes in parameters of EES. The proposed methodology opens a new direction for quantitative evaluation of the spinal cord hemodynamic in understanding the mechanisms of spinal cord functional organization and effect of neuromodulation.

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Enabling Task-Specific Volitional Motor Functions via Spinal Cord Neuromodulation in a Human With Paraplegia

Cited by 175 publications

References 36 publications

Segment-specific orientation of the dorsal and ventral roots for precise therapeutic targeting of human spinal cord

Segment-specific orientation of the dorsal and ventral roots for precise therapeutic targeting of human spinal cord

Multifactorial motor behavior assessment for real-time evaluation of emerging therapeutics to treat neurologic impairments

Changes in spinal cord hemodynamic reflect modulation of spinal network with different parameters of epidural stimulation

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